The Benefit of Combinations of Oximes for the Reactivating and Therapeutic Efficacy of Antidotal Treatment of Sarin Poisoning in Rats and Mice

Abstract

The influence of the combinations of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute sarin poisoning was evaluated in this study. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate sarin-inhibited acetylcholinesterase and reduce acute toxicity of sarin was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. Studies determining percentage of reactivation of sarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of the combination of oximes involving HI-6 and K203 is slightly higher than the reactivating efficacy of the most effective individual oxime in diaphragm and brain but the difference between them is not significant. The ability of combination of oximes involving HI-6 and trimedoxime to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating effects of the most effective individual oxime in blood as well as tissues. Moreover, both combinations of oximes were found to be as efficacious in the reduction of acute lethal toxic effects in sarin-poisoned mice as the most effective individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the oxime HI-6 is markedly more effective than the oxime K203 and trimedoxime. Based on the obtained data, we conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the ability of the most effective individual oxime (HI-6) to reactivate sarin-inhibited rat acetylcholinesterase and to reduce acute toxicity of sarin in mice.

The benefit of combinations of oximes for the ability of antidotal treatment to counteract sarin-induced brain damage in rats

“…Particularly, the combination of HI-6 and K203 appears to be the most effective to protect experimental animals from acute sarin-induced neuropathological changes in surviving animals. This conclusion corresponds to the previously published results demonstrating the benefit of combinations of oximes for the reactivating and therapeutic efficacy of antidotal treatment of sarin poisoning in rats and mice [ 18 ]. Based on the described results, both trimedoxime and K203 do not interfere with HI-6 bioavailability but rather support its action.…”

“…In our model, we utilized bispyridinium oximes. Although the bispyridinium oximes poorly penetrate across the blood-brain barrier, they are able to reactivate sarin-inhibited AChE not only at the peripheral compartment but also in the brain when they are administered at equitoxic doses corresponding to 5% of their LD 50 values at 1 min after the administration of sarin [ 14 , 18 , 19 ]. According to our results, all three therapeutic regimes mitigated the extent of sarin-induced brain injury.…”

Chemical Warfare: Perspectives on Reactivating the Enzyme Acetylcholinesterase Inhibited by Organophosphates

“…The complex soman-AChE, for example, is highly resistant to reactivation, while the complexes XV-AChE and sarin-AChE can be reactivated by a series of different compounds [20]. In the last century several oximes were synthesized and tested as antidotes against neurotoxic agents but, unfortunately, none of them showed to be efficient with all of them [35][36][37][38]. This confirms the importance of the search for new oximes.…”

Chemical Warfare: Perspectives on Reactivating the Enzyme Acetylcholinesterase Inhibited by Organophosphates

“…Porém, infelizmente, ainda não se encontrou uma oxima universal que seja eficiente com qualquer neurotóxico. 35,36 Isto confirma a importância da busca por novas oximas mais eficazes contra esses agentes.…”